Unintended benefit of anabolic steroid use in hemophilia B leiden

Abstract

Darinaparsin is a novel organic arsenic compound that is being developed to improve the efficacy and therapeutic index of arsenic as an antineoplastic agent. It has activity in preclinical models of hematological malignancies and we set out to test it in patients with refractory lymphoma. In this multicenter, Phase II trial, patients with relapsed or refractory Hodgkin (HL) and non-Hodgkin lymphoma (NHL) were treated with darinaparsin 300 mg/m 2 intravenously daily for five consecutive days every 28 days, for up to six cycles. The primary endpoint was the overall response rate. Twenty-nine heavily pretreated patients with lymphoma (22 with NHL and 7 with HL) were enrolled. There was one complete response (CR), one unconfirmed CR (CRu), three partial responses (PRs), and four with stable disease (SD), with an overall response rate of 17% (95% confidence interval (CI) 6-36%). Among the seven patients with peripheral T-cell lymphoma (PTCL), there was one CR, one CRu, and two with prolonged SD. The most common toxicities were fatigue, nausea, diarrhea, and anemia. Darinaparsin was safe and showed preliminary activity in this heavily pretreated population of relapsed/refractory lymphoma patients. Encouraging responses were seen in PTCL and further study in this subtype is planned. An estimated 74,030 people in the United States are diagnosed with HL or NHL every year with a global disease burden of approximately 350,000 new cases per year [1,2]. Major advances have been made over the last few decades in the treatment of these disorders in the form of combination chemotherapy, monoclonal antibody therapy, and stem cell transplantation [3-5], resulting in cure for a substantial proportion of cases. However, there remains a subgroup of patients who do not respond to standard therapy or relapse after an initial response. PTCL accounts for 7-10% of NHL cases and is a particularly unfavorable subtype [6]. Combination chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) is the usual treatment approach for PTCL, but outcomes are generally poor even with more intensive regimens [7]. Darinaparsin (N-[S-(dimethylarsino)-N-L-gamma-glutamyl-L-cysteinyl]-glycine; S-dimethylarsino-glutathione, ZIO-101, Zinapar TM) is a novel organic arsenic molecule consisting of dimethylated arsenic conjugated to glutathione [8]. Darinaparsin achieves higher intracellular levels compared to inorganic arsenic trioxide (ATO), and has activity in vitro against leukemia, myeloma, lymphoma, and various solid tumor cell lines [9,10]. Darinaparsin's multifaceted mechanisms of action include disruption of mitochondrial functions, increase in reactive oxygen species (ROS), and effects on signal transduction. Darinaparsin induces cell cycle arrest and apoptosis and has potent anti-angiogenic activity [11]. Unlike ATO, darinaparsin lacks affinity for the ABCC1 efflux proteins and is cytotoxic to certain ATO-resistant cell lines [12]. While other arsenicals have been used clinically, particularly for the treatment of acute promye...

A CpG Mutational Hotspot in a ONECUT Binding Site Accounts for the Prevalent Variant of Hemophilia B Leyden

“…3 Sufferers of hemophilia B Leyden express low levels of F9 up until puberty, at which point F9 levels rise and clinical symptoms improve; this phenomenon is associated with increasing androgen receptor and growth-factor activity. [4][5][6][7][8] To date, more than 80 families affected by hemophilia B Leyden have been analyzed worldwide and 21 distinct point mutations have been detected in the F9 promoter ( Figure 1). 12,13 The mutations fall into three clusters: one at nucleotide À20 relative to the transcription start site (TSS, designated þ1), one at around nucleotide þ10, and one at nucleotides -5 and -6 (À5/À6 site).…”

Część I: Wytyczne postępowania w hemofilii A i B niepowikłanej inhibitorem czynnika VIII i IX (wydanie zaktualizowane)

“…Ta postać hemofilii B objawia się we wczesnym dzieciństwie całkowitym brakiem FIX, ale w trakcie osobniczego dojrzewania aktywność FIX w osoczu zwiększa się, by w niektórych przypadkach trwale osiągnąć wartość prawidłową. Pojawienie się ekspresji genu w tym przypadku jest prawdopodobnie indukowane przez androgeny lub hormon wzrostu, lecz mechanizm tego zjawiska nie został dotąd wyjaśniony [15,16].…”